Translational studies of cellular senescence as a regulator of doxorubicin-mediated arterial dysfunction

细胞衰老作为阿霉素介导的动脉功能障碍调节剂的转化研究

• 批准号: 10616523
• 负责人: Zachary S. Clayton
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616523
• 关键词: Acceleration; Address; Advanced Glycosylation End Products; Advisory Committees; Age; Antioxidants; Aorta; Arteries; Atherosclerosis; Atomic Force Microscopy; Award; Biological Availability; Blood Vessels; Cancer Patient; Cancer Survivor; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Carotid Arteries; Cell Aging; Cell Culture Techniques; Cell Cycle Arrest; Cells; Cessation of life; Circulation; Clinical; Collagen; Data; Deposition; Doxorubicin; Elasticity; Elastin; Endothelial Cells; Endothelium; Event; Extramural Activities; Faculty; Female; Femur; Functional disorder; Funding; Future; Genes; Genetic; Human; Impairment; Inflammation; Inflammatory; Infusion procedures; Institution; International; Intervention; Laboratories; Learning; Measures; Mediating; Mentors; Mitochondria; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Oncology; Oxidative Stress; Phenotype; Physiologic pulse; Plasma; Plasma Exchange; Positioning Attribute; Postdoctoral Fellow; Process; Production; Reactive Oxygen Species; Recording of previous events; Research; Research Personnel; Research Priority; Risk Reduction; Role; Scientist; Smooth Muscle Myocytes; Source; Structural Protein; Technical Expertise; Training; Translating; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelium; Vascular Smooth Muscle; Woman; brachial artery; cancer therapy; cardiovascular disorder risk; cardiovascular risk factor; career development; chemotherapeutic agent; chemotherapy; crosslink; experimental study; follow-up; heart function; improved; in vivo; innovation; insight; male; member; men; mortality; mouse model; new therapeutic target; novel; pharmacologic; pre-clinical; preservation; prevent; response; seal; senescence; sex; skills; small hairpin RNA; tenure track; translational study; young adult

PROJECT SUMMARY/ABSTRACT The purpose of this K99/R00 application is to provide support for Dr. Zachary Clayton, a promising post- doctoral fellow in the laboratory of Dr. Douglas Seals. This additional research and training will allow him to successfully transition into an independent investigator in the field of translational cardiovascular (CV) physiology. As part of his proposed K99 training plan, he will learn new technical skills, enhance his intellectual and professional skills and participate in various career development activities, including those that will help establish him as a leader in the fields of cardio-oncology and cellular senescence. His proposed project seeks to investigate the role of cellular senescence in regulating arterial dysfunction (i.e. the primary risk factor for CV diseases [CVD]) with the common chemotherapeutic agent Doxorubicin (DOXO), first in mice (K99) and later translating to mice and humans (R00). Senescent cells accumulate in the CV system following DOXO and cellular senescence may exacerbate upstream regulators of arterial dysfunction (i.e. inflammation and oxidative stress). Guided by strong preliminary data, Dr. Clayton will first (Aim 1) confirm that DOXO causes arterial dysfunction via cellular senescence by utilizing complementary mouse models in which he can systemically clear senescent cells. With guidance and training in technical skills from an internationally recognized expert in cellular senescence, he will then (Aim 2) conduct innovative ex vivo cell culture experiments in vascular cells to determine the role of cellular senescence in mediating key phenotypes underlying arterial dysfunction, evoked by plasma from DOXO-treated mice. After transitioning to a faculty position, Dr. Clayton will next (Aim 3; R00) translate his findings first to mice, by performing mouse-to-mouse plasma exchange experiments to determine whether DOXO-mediated arterial dysfunction can be transferred via the circulation and whether this response is dependent upon cellular senescence activation. Next, he will extend his findings to humans by determining the role of plasma from DOXO-treated cancer patients in facilitating arterial dysfunction-related phenotypes in cultured vascular cells. Overall, the proposed research has the potential to address 2 strategic research priorities of NHLBI: 1) investigate new pathobiological mechanisms important to the onset of CVD; 2) determine strategies for reducing vascular morbidity in cancer survivors. The proposed projects will provide opportunities for future fundable research, culminating in submission of a novel R01 during years 4-5 of this award. Dr. Seals (primary mentor) is an internationally recognized and NIH funded scientist with a strong history of successful mentoring in translational CV research. With his guidance and the guidance of co-mentor Dr. Judith Campisi, advisory team members Drs. Youngho Bae, Thomas LaRocca, Saul Villeda, Lavanya Kondapalli, Kamali Kimdar and biostatistician Dr. Zhiying You, Dr. Clayton will be able to successfully complete the proposed research and training plan and transition to an independent, extramurally-funded tenure-track position at a top-tier (R1) research institution.

项目概要/摘要 此 K99/R00 申请的目的是为 Zachary Clayton 博士提供支持，他是一位有前途的后 道格拉斯·西尔斯博士实验室的博士研究员。这些额外的研究和培训将使他能够 成功转型为转化心血管（CV）领域的独立研究者 生理。作为他提出的 K99 培训计划的一部分，他将学习新的技术技能，增强智力 和专业技能，并参加各种职业发展活动，包括那些有助于 使他成为心脏病肿瘤学和细胞衰老领域的领导者。他提出的项目寻求 研究细胞衰老在调节动脉功能障碍中的作用（即主要危险因素 使用常见化疗药物阿霉素 (DOXO) 治疗心血管疾病 [CVD]），首先在小鼠中使用 (K99) 后来翻译成小鼠和人类（R00）。 DOXO 后衰老细胞在 CV 系统中积聚 细胞衰老可能会加剧动脉功能障碍的上游调节因子（即炎症和 氧化应激）。在强有力的初步数据的指导下，Clayton 博士将首先（目标 1）确认 DOXO 会导致 通过利用互补的小鼠模型，他可以通过细胞衰老来治疗动脉功能障碍 系统性清除衰老细胞。接受国际专家的技术技能指导和培训 作为公认的细胞衰老专家，他将（目标 2）进行创新的离体细胞培养 血管细胞实验以确定细胞衰老在介导关键表型中的作用 潜在的动脉功能障碍，由 DOXO 治疗小鼠的血浆引起。转为教师后 接下来，Clayton 博士（目标 3；R00）将通过进行小鼠对小鼠实验，首先将他的发现转化为小鼠 血浆交换实验以确定 DOXO 介导的动脉功能障碍是否可以转移 通过循环以及这种反应是否依赖于细胞衰老激活。接下来，他将 通过确定接受 DOXO 治疗的癌症患者的血浆在 促进培养的血管细胞中动脉功能障碍相关的表型。总体而言，拟议的研究 有潜力解决 NHLBI 的 2 个战略研究重点：1）研究新的病理生物学 CVD 发生的重要机制； 2) 确定降低癌症血管发病率的策略 幸存者。拟议的项目将为未来可资助的研究提供机会，最终 在该奖项的第 4-5 年期间提交小说 R01。 Seals 博士（主要导师）是一位国际 受到 NIH 资助的公认科学家，在转化型 CV 研究方面拥有成功指导的悠久历史。 在他和联合导师 Judith Campisi 博士的指导下，顾问团队成员 Drs.英浩 Bae、Thomas LaRocca、Saul Villeda、Lavanya Kondapalli、Kamali Kimdar 和生物统计学家 Jiying You 博士， 克莱顿博士将能够成功完成拟议的研究和培训计划，并过渡到 在顶级 (R1) 研究机构获得独立、外部资助的终身教授职位。

项目成果

Favourable alterations in adipose remodelling induced by exercise training without weight loss: exploring the role of microvascular endothelial function.

不减肥的运动训练引起的脂肪重塑的有利改变：探索微血管内皮功能的作用。

• 发表时间: 2022-08
• 作者: Maurer, Grace S;Clayton, Zachary S
• 通讯作者: Clayton, Zachary S

The plasma metabolome is associated with preservation of physiological function following lifelong aerobic exercise in mice.

血浆代谢组与小鼠终生有氧运动后生理功能的保存有关。

• 发表时间: 2024-06
• 影响因子: 5.6
• 作者: Murray, Kevin O;Maurer, Grace S;Gioscia;Zigler, Melanie C;Ludwig, Katelyn R;D'Alessandro, Angelo;Reisz, Julie A;Rossman, Matthew J;Seals, Douglas R;Clayton, Zachary S
• 通讯作者: Clayton, Zachary S